Cerebral temperature control

ABSTRACT

The present invention relates to a method and equipment for controlling the temperature of the brain or brain hemisphere. More specifically the present invention refers to a method and equipment for quick and efficient control of the temperature of the brain and for maintaining a low temperature in the brain. The inventive concept can be divided into three phases. Firstly, an emergency whole body temperature control phase providing a quick temperature control at for example a scene of accident. Secondly, a brain-selective temperature control phase providing a more efficient temperature control at for example an emergency room and thirdly, a maintained temperature control phase providing an even more efficient temperature control for a selected period of time.

TECHNICAL FIELD

The present invention relates to a method and equipment for controllingthe temperature of a brain of a living being.

BACKGROUND OF THE INVENTION

In pathological conditions, the body temperature or the temperature ofthe body parts of a living being influences the healing process and therisk of permanent damage. Cancer cells, for example, are heat sensitiveand a local heating of the blood flow around a cancer tumor may for sometypes of cancer constitute a treatment resulting in restrained tumorgrowth, or in some cases even in a shrinking of the tumor. In othercases cooling of a body part may be important to reduce adversesecondary symptoms of the pathological condition.

In the case of a stroke, the blood flow in the brain is reduced due to ahemorrhage or the clogging of a blood vessel. This condition is criticaland it is important that treatment is initiated at an early stage, toreduce the loss of bodily functions, such as paralysis. It is well knownthat cooling the brain effectively blocks the development of cellulardamage after an episode of ischemia. Cooling of the patient thereforealso results in a reduction of the symptoms of neurological deficit.However, there are certain problems associated with the cooling of anentire patient. One is that the cooling takes a considerable amount oftime, another that it must be carried out under close control of vitalsigns or under anesthesia, and a third that there is a risk ofcardiovascular complications.

In the case of a circulatory arrest, the brain can suffer permanentdamage if the arrest exceeds a time period of about 5-15 minutes.However, if the temperature of the brain is lowered before or after thearrest the brain damage is diminished. This may also be applied to thesituation of neonatal asphyxia.

In the case of brain trauma the brain suffers from open or close headconcussion. Hypothermia has been shown to diminish traumatic braininjury in such cases.

There are several methods in the prior art to carry out a more isolatedcooling of a single organ or body part. An example of cooling of thebrain in a human being is disclosed in the patent document WO 98/23917,relating to a method of cerebral retro-perfusion and retro-infusion,involving the cooling of arterial blood that then is returned to theentire brain. However, this method entails a large and complicatedsurgical procedure, which delays the onset of an actual treatment.

The U.S. Pat. No. 5,906,588 discloses a method and a device forheart-lung bypass and cooling of a specific body part. This disclosureprimarily relates to complicated heart surgery and organtransplantation.

Today there is no safe and simple method disclosed for a rapid inductionof brain hypothermia in ischemic disease.

PURPOSE OF THE INVENTION

A purpose of the present invention is to provide a system and a methodfor quick and efficient control of the temperature of the brain and aroute for fast delivery of drugs to the brain. An aim of the inventionis to provide a system and a method that is simple and initially doesnot require specialized personnel acquainted with for example radiologyor other diagnostic imaging techniques.

Another purpose of the invention is to provide a system and a method forquick and simple temperature control that also supports subsequentdiagnostic measures such as magnetic resonance imaging (MRI), i.e.temperature control without inserting metal components into the body ofthe patient.

Yet another purpose of the invention is to provide a system and a methodfor maintaining the temperature control of the brain.

BRIEF DESCRIPTION OF THE INVENTION

According to the invention the purpose indicated above is achieved by ina first phase, cf. FIG. 1 a, introducing an infusion catheter forinfusion of a temperature controlled infusion solution or perfusate intoa vein initiating a quick general body hypothermia.

In an optional second phase of the invention a second infusion catheteris introduced into an artery of the living being. The second infusioncatheter is configured to provide selective temperature control of thebrain and infusion of other important substrates and pharmacologicalcompounds into the brain. This accomplishes a quick temperature changein the brain, involving only a comparatively minor procedure.

When treating for example a case of stroke, the brain and thus also theaffected brain hemisphere can be cooled quickly according to the methodof the invention, resulting in a reduction of the symptoms of functionalloss. Preferably, continued cooling is maintained in order to keep thetemperature of the brain lowered for as long as it takes to diagnose,medicate and restore the functions of the ischemic brain section.

A further embodiment and possibly a third phase of the inventioninvolves cooling or heating, of blood withdrawn from a living beingbefore the blood is recycled to the living being. In this embodiment anextra-corporeal circuit or conduit is established. In one embodiment theextra-corporeal circuit is established between a vein, e.g. a vein inthe lower part of the body, and an artery, e.g. the arteria carotiscommunis, sinister or dexter, arteria subclavia, brachiocephalic trunk,or some other artery, e.g. an artery that supplies blood to the brain,wherein the temperature of the blood is modified outside the body beforethe blood is returned to the body through the artery.

Another embodiment contains the method to reintroduce heated blood tothe venous system in order to avoid whole body hypothermia. Thisembodiment thus allows for heating a first part of the body at the sametime as a second part, for example the brain, is cooled. The system forperforming this embodiment preferably comprises two separate flowbranches or circuits, one for the cooling and one for the heating.

Yet another embodiment of the invention involves, in addition to coolingor heating the blood, controlling the oxygenation of the brain and theaffected brain hemisphere, i.e. the blood is oxygenated or deoxygenatedbefore it is returned to the body.

The invention comprises a system, equipment components and a method ininter alia the following aspects of the invention:

A method for brain hypothermia, said method comprising, in a first phaseto enable an early and fast onset of the hypothermia, the steps of:

-   -   providing a container with an infusion solution having a first        temperature and a venous infusion catheter connected to an        outlet of said container, said venous infusion catheter having        an infusion solution lumen;    -   percutaneously inserting a distal end of said venous infusion        catheter into a peripheral vein;    -   cooling the infusion solution to a second temperature lower than        said first temperature; and    -   infusing a first amount of said cold infusion solution into said        vein via the infusion solution lumen of said venous infusion        catheter shortly after said cooling, to enable the cold infusion        solution to cool the blood flowing to the brain while avoiding        air bubbles arising in the infusion solution.

Varieties of this method further comprises a second hypothermia phasefor brain-selective hypothermia, wherein an arterial infusion catheteris inserted into an artery and a second amount of cold solution isinfused into the arterial system, to enable a more efficient temperatureregulation of the brain.

The arterial infusion catheter is inserted into a selected peripheralartery, e.g. an arteria radialis, arteria ulnaris or an arteriabrachialis. The method may further comprise the step of positioning adistal tip of said arterial infusion catheter in a selected centralartery at the vicinity of a branch artery supplying blood to the brain.The selected central artery is e.g. arteria subclavia at the vicinity ofarteria carotis, truncus brachiocephalicus or ascending aorta. In somecases it may be necessary or improving to apply a pressure from theoutside of the extremity with the peripheral artery for decreasingperipheral blood circulation.

Further embodiments comprise the steps of:

-   -   percutaneously inserting a temperature sensor in a blood vessel        draining blood from the brain;    -   sensing the temperature in the blood of said blood vessel thus        providing an indication of the temperature in the brain or        selected parts of the brain;    -   adjusting the infusion rate dependent on said sensed temperature        for achieving a desired temperature in the brain.

In one embodiment the emergency phase may be directly followed by ahypothermia phase for maintained hypothermia, comprising the steps of:

-   -   inserting into a blood vessel an extraction catheter for        extraction of blood;    -   inserting an arterial infusion catheter in or in the vicinity of        an artery supplying blood to the brain;    -   establishing an first extra-corporeal blood circuit for cooled        blood between said extraction catheter and said arterial        infusion catheter via a pumping means and a temperature        regulating device capable of cooling extracted blood;    -   extracting blood from said blood vessel via said extraction        catheter leading a first amount of said extracted blood into        said first extra-corporeal blood circuit;    -   cooling said first amount of said extracted blood;    -   infusing said cooled extracted blood to said brain supplying        artery via said arterial infusion catheter;    -   maintaining cooling and circulation in said first        extra-corporeal blood circuit for a selected period of time.

A further developed embodiment comprises the steps of:

-   -   inserting a venous infusion catheter into a vein of the venous        system;    -   establishing a second extra-corporeal blood circuit for heated        blood between said extraction catheter and said venous infusion        catheter via said pumping means and a heating device capable of        heating extracted blood;    -   leading a second amount of said extracted blood from said blood        vessel via said extraction catheter into said second        extra-corporeal blood circuit;    -   heating said second amount of said extracted blood;    -   infusing said heated second amount of extracted blood to said        venous system via said venous infusion catheter;    -   maintaining heating and circulation in said second        extra-corporeal blood circuit for a selected period of time.

For regulating the temperature this method embodiment further comprisesthe steps of:

-   -   percutaneously inserting a temperature sensor in a blood vessel        draining blood from the brain;    -   sensing the temperature in the blood of said blood vessel thus        providing an indication of the temperature in the brain or in a        part of it;    -   adjusting the infusion rate of said cooled blood dependent on        said sensed temperature for achieving a desired temperature in        the brain, or the steps of:    -   percutaneously inserting a temperature sensor in a blood vessel        draining blood from the brain;    -   sensing the temperature in the blood of said blood vessel thus        providing an indication of the temperature in the brain;    -   adjusting the temperature of said cooled blood dependent on said        sensed temperature for achieving a desired temperature in the        brain.

One embodiment comprises a third hypothermia phase for maintainedhypothermia or follows the brain-selective hypothermia phase, the thirdhypothermia phase comprising the steps of:

-   -   inserting into a blood vessel an extraction catheter for        extraction of blood;    -   inserting the tip of an optional arterial infusion catheter in        or in the vicinity of an artery supplying blood to the brain;    -   establishing a first extra-corporeal blood circuit for cooled        blood between said extraction catheter and said arterial        infusion catheter via a pumping means and a temperature        regulating device capable of cooling extracted blood;    -   extracting blood from said blood vessel via said extraction        catheter leading a first amount of said extracted blood into        said first extra-corporeal blood circuit;    -   cooling said first amount of said extracted blood;    -   infusing said cooled extracted blood to said brain supplying        artery via said arterial infusion catheter;    -   maintaining cooling and circulation in said first        extra-corporeal blood circuit for a selected period of time, and        possibly also the steps of:    -   inserting a venous infusion catheter into a vein of the venous        system;    -   establishing a second extra-corporeal blood circuit for heated        blood between said extraction catheter and said venous infusion        catheter via said pumping means and a heating device capable of        heating extracted blood;    -   leading a second amount of said extracted blood from said blood        vessel via said extraction catheter into said second        extra-corporeal blood circuit;    -   heating said second amount of said extracted blood;    -   infusing said heated second amount of extracted blood to said        venous system via said venous infusion catheter;    -   maintaining heating and circulation in said second        extra-corporeal blood circuit for a selected period of time.

In its most basic form an embodiment of the emergency phase methodcomprises the steps of:

-   -   providing a container with a cold infusion solution and an        infusion catheter connected to an outlet of said container, said        infusion catheter having an infusion solution lumen;    -   percutaneously inserting a distal end of said infusion catheter        into a blood vessel;    -   infusing the cold infusion solution into said blood vessel, to        enable the cold infusion solution to flow distally to the brain;    -   or alternatively phrased, infusing a solution having a first        predetermined temperature into a blood vessel until the body has        reached a predetermined temperature or a predetermined maximum        amount of solution has been infused.

An embodiment of an equipment for brain hypothermia in a living being,comprises:

-   -   a container of infusion solution;    -   a temperature regulating apparatus for said infusion solution;    -   a flexible elongated infusion catheter, said catheter having a        proximal end being attachable to an outlet of said container,        said catheter having a sufficiently small diameter to be        percutaneously insertable into a blood vessel and its tip        forwarded to or into the vicinity of the blood vessel feeding        the brain with blood so that the infusion solution will find its        way to the brain.

Other aspects of the invention include:

An equipment for brain hypothermia, said equipment comprising, to enablean early and fast onset of the hypothermia:

-   -   a container with an infusion solution having a first temperature        and a venous infusion catheter being connectable to an outlet of        said container, said venous infusion catheter having an infusion        solution lumen;    -   said venous infusion catheter having a distal end devised to be        percutaneously inserted into a peripheral vein;    -   a cooling device being configured for cooling the infusion        solution to a second temperature lower than said first        temperature;    -   wherein the cooling device is configured for cooling the        infusion solution to a second temperature in the range of 0-37        degrees Celsius;    -   wherein the cooling device is configured for cooling the        infusion solution to a second temperature in the range of 0-4        degrees Celsius;    -   wherein the infusion catheter is configured to be inserted into        a median cubital vein:    -   wherein the infusion catheter is configured to be inserted into        a saphenous vein;    -   wherein the infusion solution is a hypotonic saline solution;    -   wherein said first amount of infusion solution is in the range        of 1-2 liters or in the range of 10-60 ml/kg;    -   wherein the infusion solution has an altered osmolarity, e.g. a        low osmolarity, in order to lessen the circulatory volume load        of the infusion solution when infused into the patient;    -   wherein the infusion solution is provided in a container that is        air-sealed at steady state at a temperature in the range of 37        degrees Celsius;    -   the equipment further comprising a container with gas or a gas        mixture having brain protective properties and equipment for        inhaling a controlled fraction of said gas.

An embodiment for equipment configured use in a brain-selectivehypothermia phase comprises an arterial infusion catheter configured tobe inserted into an artery and a container with a second amount of coldsolution configured to be infused into the arterial system, to enable amore efficient temperature regulation of the brain in a secondhypothermia phase for brain-selective hypothermia.

In different embodiments this equipment:

-   -   the arterial infusion catheter is configured to be inserted into        a selected peripheral artery;    -   wherein the arterial infusion catheter is configured to be        inserted into an arteria radialis; arteria ulnaris or an arteria        brachialis;    -   wherein said arterial infusion catheter further is configured to        the positioning of a distal tip of said arterial infusion        catheter in a selected central artery at the vicinity of a        branch artery supplying blood to the brain, wherein said        selected central artery is arteria subclavia at the vicinity of        arteria carotis, truncus brachiocephalius or ascending aorta.

Embodiments may further comprise a device for applying a pressure fromthe outside of the extremity with the peripheral artery for decreasingperipheral blood circulation. Further embodiments further comprises:

-   -   a temperature sensor configured to be percutaneously inserted in        a blood vessel draining blood from the brain; and being        configured to:    -   sensing the temperature in the blood of said blood vessel thus        providing an indication of the temperature in the brain; and    -   adjusting the infusion rate dependent on said sensed temperature        for achieving a desired temperature in the brain.

A further developed embodiment is followed by a third hypothermia phasefor maintained hypothermia, and comprises:

-   -   an extraction catheter being configured to be inserted into a        blood vessel for extraction of blood;    -   an arterial infusion catheter being configured to be inserted        into the vicinity of an artery supplying blood to the brain:    -   coupling means for establishing a first extra-corporeal blood        circuit for cooled blood between said extraction catheter and        said arterial infusion catheter via a pumping means and a        temperature regulating device capable of cooling extracted        blood; and being configured to:    -   extracting blood from said blood vessel via said extraction        catheter leading a first amount of said extracted blood into        said first extra-corporeal blood circuit;    -   cooling said first amount of said extracted blood;    -   infusing said cooled extracted blood to said brain supplying        artery via said arterial infusion catheter;    -   maintaining cooling and circulation in said first        extra-corporeal blood circuit for a selected period of time; and        possibly further comprising:    -   a venous infusion catheter being configured to be inserted into        a vein of the venous system; and further being configured to:    -   establishing a second extra-corporeal blood circuit for heated        blood between said extraction catheter and said venous infusion        catheter via said pumping means and a heating device capable of        heating extracted blood;    -   leading a second amount of said extracted blood from said blood        vessel via said extraction catheter into said second        extra-corporeal blood circuit;    -   heating said second amount of said extracted blood;    -   infusing said heated second amount of extracted blood to said        venous system via said venous infusion catheter;    -   maintaining heating and circulation in said second        extra-corporeal blood circuit for a selected period of time.

In this embodiment a temperature sensor would be configured to adjustingthe infusion rate of said cooled blood dependent on said sensedtemperature for achieving a desired temperature in the brain; or toadjusting the temperature of said cooled blood dependent on said sensedtemperature for achieving a desired temperature in the brain.

An embodiment of an equipment for brain hypothermia comprises, to enablea brain-selective hypothermia:

-   -   a container with an infusion solution having a first temperature        and an arterial infusion catheter connectable to an outlet of        said container, said arterial infusion catheter having an        infusion solution lumen;    -   a distal end of said arterial infusion catheter being configured        to be percutaneously inserted into an artery in or in the        vicinity of a branch artery supplying blood to the brain;    -   a cooling device configured to cooling the infusion solution to        a second temperature lower than said first temperature, to        enable the cold infusion solution to cool the blood flowing to        the brain while avoiding air bubbles arising, in the infusion        solution and an efficient temperature regulation of the brain.

An embodiment of equipment for brain hypothermia comprises, to enable amaintained hypothermia:

-   -   an extraction catheter configured to be inserted into a blood        vessel for extraction of blood;    -   an arterial infusion catheter configured to be inserted in an        artery into the vicinity of an artery supplying blood to the        brain;    -   means for establishing an second extra-corporeal blood circuit        for cooled blood between said extraction catheter and said        arterial infusion catheter via a pumping means and a cooling,        device capable of cooling, extracted blood;    -   a venous infusion catheter being, configured to be inserted into        a vein of the venous system;    -   means for establishing a first extra-corporeal blood circuit for        heated blood between said extraction catheter and said venous        infusion catheter via said pumping, means and a heating device        capable of heating extracted blood;    -   means for extracting blood from said blood vessel via said        extraction catheter into said first and second extra-corporeal        blood circuit;    -   a cooling, device for cooling a second amount of said extracted        blood;    -   a heating, device for heating a first amount of said extracted        blood; and being configured to:    -   infusing said cooled second amount of extracted blood to said        brain supplying artery via said arterial infusion catheter:    -   infusing, said heated first amount of extracted blood to said        venous system via said venous infusion catheter.

A basic embodiment of an equipment for brain hypothermia, comprises:

-   -   a container with a cold infusion solution and an infusion        catheter connectable to an outlet of said container, said        infusion catheter having, an infusion solution lumen;    -   a distal end of said infusion catheter being configured to be        percutaneously inserted into a blood vessel that supplies the        brain with blood;    -   and being configured to infusing, the cold infusion solution        into said blood vessel, to enable the cold infusion solution to        flow distally to the brain.    -   A specifically developed catheter, wherein: the catheter being,        configured to assume a curvature at its distal part; comprises    -   a first lumen having a plurality of openings positioned close to        a distal end of the catheter and at the outer arc of the        curvature:    -   a second lumen having an opening, at the tip of the distal end        of the catheter;    -   a distal part of the catheter tapering from said plurality of        openings to said tip of the catheter.

DESCRIPTION OF THE DRAWINGS

The present invention will be described in further detail below, withreference to the accompanying drawings, of which

FIG. 1 a is a block diagram indicating three phases for regulating thebrain temperature according to embodiments of the invention;

FIG. 1 b is a block diagram indicating the steps of a method accordingto one embodiment of the invention;

FIG. 2 is a schematic illustration of an example of a first embodimentof the system according to the invention, here also called the emergencywhole body control phase;

FIG. 3 a is a block diagram indicating the steps of a method accordingto one embodiment of the invention;

FIG. 3 b illustrates schematically an example of how a catheter isarranged in the arteria subclavia dexter, in a second embodiment of thesystem according to the invention, here also called the brain selectivetemperature control phase;

FIG. 4 is a block diagram indicating the steps of a method according toone embodiment of the invention;

FIG. 5 shows schematically an example of a double lumen catheterapplicable in embodiments of the invention;

FIG. 6 a illustrates schematically a first example of a the inventivesystem configured in an embodiment here called the maintainedtemperature control phase;

FIG. 6 b illustrates schematically a second embodiment of the inventivesystem configured in an embodiment of the maintained temperature controlphase;

FIG. 6 c illustrates schematically a third embodiment of the inventivesystem configured in an embodiment of the maintained temperature controlphase;

FIG. 7 a, 7 b and 7 c show schematically embodiments of a temperatureregulating device;

FIG. 8 illustrates schematically an embodiment of an extra-corporealblood circuit comprising a shunt; and

FIG. 9 shows schematically an example of a triple lumen catheterapplicable in embodiments of the invention.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a method, a system and a set ofdisposable equipment components for controlling the temperature of thebrain of a living being. More specifically the present invention refersto a method, a system, and a set of disposable equipment foraccomplishing a simple, quick and efficient control of the temperatureof a brain. The method according to the invention for accomplishingcontrol of the temperature of the brain and maintaining the control ofthe temperature during a predetermined period of time can be dividedinto three phases or procedures. Firstly, an emergency whole bodytemperature control phase, secondly, a brain selective temperaturecontrol phase and thirdly, a maintained temperature control phase.

Below, the invention will be explained by reference to examples ofembodiments thereof, primarily relating to cooling the brain in a caseof stroke, trauma or neonatal asphyxia, or before, during or after acirculatory arrest in a human patient. In some embodiments of theinvention the control of the temperature is performed in conjunctionwith another treatment procedure, such as infusion or inhalation ofpharmaceuticals, a gas or a gas mixture, respectively that have brainprotective properties. Examples of such gases are different anaestheticgases such as Isofluran or hydrogen gas. By substances having brainprotective properties it is here understood such substances that:

-   -   decreases the effects of the occurrence of free radicals, that        is a substance scavenging free radicals;    -   decreases the activation of leukocytes;    -   decreases inflammatory reactions;    -   preventing the detrimental cell signaling;    -   enhancing DNA repair;    -   preventing dysfunction of mitochondria, endoplastic reticulum        (ER), plasma membrane and lysosome;    -   inhibiting proteases and lipases; or    -   normalizing lipid metabolism.

There is also a brain protective effect in adding gas or gas mixture inorder to optimize, for example decreasing the partial pressure ofoxygen.

As mentioned above, in the case of a living being suffering from astroke or being in a state of resuscitation from circulatory arrest, itis very important to provide a quick cooling of the brain in order tominimize the brain damages due to the reduced or loss of blood supply tothe brain. Thus, it is important to provide a method for simple andquick temperature control of the brain that may be performed by nursingor ambulance personnel at for example the scene of an accident or at ahospital. In any case, it is obvious to a person skilled in the art thatthe invention can be adapted to different uses within the scope of theindependent claims.

The Emergency Whole Body Temperature Control Phase

To achieve a quick thermal regulation of the selected brain hemisphere,the perfusion may initially consist of some perfusion solution, such asa saline solution, Ringer's lactate or Ringer's acetate, containing anantioxidant or a drug, followed in a second stage by thermally regulatedblood which is returned to the patient. According to this (second)embodiment, a compression cuff, such as a tourniquet or the like, isplaced on the arm in question, i.e. the arm into which the device forreturning the blood is inserted, in order to suppress peripheralcirculation and to increase the pressure in the blood vessel, making thepressure of the returning blood equal to the pressure exerted by theheart on the blood, which in consequence results in a flow velocity of10-12 ml/s. The flow velocity may optionally be regulated in such a wayas to make the blood in the arteria vertebralis dexter and the arteriacarotis dexter perfuse with a spill-over to the arcus aortae, the flowalong the aorta curvatura major being laminar. This is desirable inorder to allow the maximum share of the spill-over to reach the aortacarotis sinister. The above arrangement will prevent flow backwardstoward the valvular section.

As soon as the thermal regulation has started, diagnostic work can beinitiated, such as magnetic resonance imaging, or some other form ofdiagnostic examination, without having to abort the thermal regulationas described above. When the periferal blood has reached the desiredtemperature, for example 32 degrees Celsius, the thermal regulationdescribed is aborted, and the temperature reached can be maintainedusing conventional cooling blankets or the like.

A simple and quick initial control of the temperature of the brain andthe body is achieved by the emergency temperature control phasecomprising in more general terms the step of initiating as soon aspossible an intravenous infusion of a solution that has a controlledtemperature, into a blood vessel of the living being by for exampleambulance personnel or other nursing staff. In this connection it ispossible to add a temperature controlled solution to the body of a humanbeing in the amount of about 10-60 ml/kg, e.g. 1 to 3 liters, or evenmore. The solution is for example a saline solution possibly comprisingantioxidant or other pharmaceuticals having anti-ischaemic properties orsuppressing inflammatory processes. In conjunction also inhalation ofselected gases can be provided, which gases may have brain-protectiveproperties. Examples of gases or gas mixtures could be differentanaesthetic gases such as Isofluran or hydrogen gas.

By substances having brain protective properties it is here understoodsuch substances that:

-   -   decreases the effects of the occurrence of free radicals, that        is a substance scavenging free radicals;    -   decreases the activation of leukocytes;    -   decreases inflammatory reactions;    -   prevents the detrimental cell signaling;    -   enhances DNA repair;    -   prevents dysfunction of mitochondria, endoplasmatic reticulum        (ER), plasma membrane and lysosome;    -   inhibits proteases and lipases; or    -   normalizes lipid metabolism.

These pharmaceuticals may include calcium blocking substances, magnesiumor Nimodipin. However, in this description text referring to the wholebody temperature control phase, we will refer to the blood vessel as avein but it could also be an artery if for example personnel that iscompetent in arterial catheterization is available. In the case ofcontrolling the temperature during a stroke or a circulatory arrest, theinfusion solution is preferably a cold or ice cold solution, e.g., asaline solution possibly comprising an antioxidant. More specifically,embodiments of the emergency temperature control phase comprises asshown in FIG. 1 b (cf. FIG. 2) the steps of: 1100 introducing,percutaneously or through a surgical cut down, an infusion catheter intoa selected peripheral blood vessel, preferably a vein 206 such as themedian cubital vein 206 or saphenous vein, or a central blood vessel208, 210, 212, 214 such as the jugular vein 210, 214 or the subclavianvein 208, 212; 1102 positioning the tip of the infusion catheter asclose to the venous inlet of the heart as possible without gettingadverse cardiac effects of the quick infusion of a temperaturecontrolled solution; 1104 controlling or regulating the temperature,e.g. cooling, of an infusion solution by means of a temperatureregulating means, e.g. a cooling means; 1106 infusing the temperaturecontrolled infusion solution, e.g., a cold or ice cold saline solution,preferably having an altered osmolarity, e.g. a low osmolarity, andcomprising for example ischemic protective pharmaceuticals into theblood vessel.

One embodiment may also possibly comprise the step of 1108 possiblyinhaling through a face mask or an endotracheal tube a controlledfraction of gas or a gas mixture with brain-protective properties.

Thus, in step 1100 an infusion catheter is introduced, preferablypercutaneously, into a selected blood vessel, preferably a vein, of theliving being such as the median cubital vein, saphenous vein, cephalicvein or basilic vein. For simplicity, the chosen venous catheter isdesigned such and of the type that the involved personnel are wellacquainted with. To achieve sufficient flow of the temperaturecontrolled solution, the inner diameter of the infusion catheter istypically in the range of 1-4 mm, preferably in the range of 2-3 mm, andthe length of the infusion catheter is at least about 3 cm. In the caseof an infusion catheter long enough to reach for example theintrathoracic space, the tip positioning according to step 1102 ispreferably performed by means of indication means such as markingsarranged on the outer surface of the infusion catheter or smalldiameter-changes of the catheter, whereby the indication means indicatesthe length of the catheter that has been introduced into the livingbeing. Thus the position of the catheter tip can be determined withoutthe use of any imaging techniques.

In step 1104 the temperature of the infusion solution is regulated orcontrolled, i.e. the infusion solution is temperature controlled. In thecase of stroke or circulatory arrest the infusion solution is preferablya cooled hypotonic saline solution, i.e. a saline solution having anosmotic pressure lower than the blood. An infusion solution having a lowosmolarity is preferably chosen in order to lessen the circulatoryvolume load of the infusion solution. In for example an ambulance, aboutone to two liters of infusion solution having a temperature in the rangeof 0-37 degrees Celsius, preferably 0-10 degrees Celsius, morepreferably in the range of 0-4 degrees Celsius, can be infused, wherebya lowered body and brain temperature is achieved. However, in somesituations it is sufficient to infuse an infusion solution having atemperature in the range of 10-37 degrees Celsius, since infusion of ainfusion solution having a temperature lower than the body temperaturewill cause a decreased brain temperature.

In one embodiment of the invention, the infusion solution is cooled bymeans of a peltier element, i.e. an apparatus which by means ofelectricity, produces cooling of a metal part in an electrical circuitwhich metal part cools the infusion solution. However, other suitablecooling means can also be used. For example, a container comprising theinfusion solution can be placed in an icebox or in a containercomprising ice or ice cubes.

However, a cooled infusion solution in steady state with the atmosphericpressure may give rise to gas bubbles or air bubbles of different sizeswhen supplied to a patient, due to the lower gas solubility at highertemperatures. Such air bubbles may be very harmful to the patient ifthey are conveyed to the brain. Thus it is important to provide a quickcooling of the solution just before the supply of the solution in orderto avoid or decrease the amount of gas or air bubbles in the infusionsolution. Another way of avoiding or decreasing the amount of airbubbles is to provide the infusion solution in a sealed or air-sealedcontainer, for example in a sealed container manufactured of a gasimpermeable plastic or a plastic-like material, and sealing performed atsteady state at a temperature in the range of 37 degrees Celsius.

Further, in step 1106 the infusion solution is infused to venous bloodby means of the infusion catheter, whereby a lowered body temperature isachieved. In one embodiment of the invention, the body temperature isdecreased by one to two degrees Celsius when one to two liters of cooledinfusion solution is infused. The infusion speed or velocity can bevaried for example by applying a pressure on the container or plasticbag comprising the infusion solution, but the infusion speed shouldpreferably be as large as possible. However, the infusion speed dependson the dimensions of the infusion catheter.

Possibly, in step 1108 a gas or a gas mixture having brain protectiveproperties is inhaled through for example a facial mask. Examples ofsuch gases are different anaesthetic gases such as NO, Isofluran andhydrogen gas. By substances having brain protective properties it ishere understood such substances that:

-   -   decreases the effects of the occurrence of free radicals, that        is a substance scavenging free radicals;    -   decreases the activation of leukocytes;    -   decreases inflammatory reactions;    -   prevents the detrimental cell signaling;    -   enhances DNA repair;    -   prevents dysfunction of mitochondria, endoplasmatic reticulum        (ER), plasma membrane and lysosome;    -   inhibits proteases and lipases; or    -   normalizes lipid metabolism.

There is also a brain protective effect in adding gas or a gas mixturein order to optimize, for example decreasing, the partial pressure ofoxygen and carbondioxide.

FIG. 2 shows this embodiment of the invention applied in a human patientfor cooling the brain. A container 201, for example a plastic bag,having a temperature controlled infusion solution 202, is coupled to aninfusion catheter 204. The infusion solution is cooled in a cooler 203before use or is maintained in a cooling box 205. In this exemplifyingfigure, the infusion catheter is percutaneously introduced into theright median vein 206 and inserted as close to the venous inlet of theheart as possible without getting adverse cardiac effects due to a quickinfusion of a cooled infusion solution. The closer the outlet of theinfusion catheter 204 is to the venous inlet of the heart the smallerthe temperature loss in the cooled infusion solution before reaching thebrain. As the emergency temperature control goes on by infusing in thiscase cooled solution, the temperature of the whole body is decreased.

In the case of heating a cold patient, the treatment would be analoguebut of course with a heated infusion solution.

The Brain-Selective Temperature Control Phase

When personnel qualified for arterial catheterization reaches thepatient, for example at a hospital, the brain-selective temperaturecontrol phase may be achieved, either as a complement to the emergencywhole body temperature control procedure or as separate temperaturecontrol procedure. As schematically shown in FIG. 3 a, thebrain-selective temperature control phase comprises the steps of: 1200possibly introducing by surgical cut-down or percutaneously with e.g.Seldinger technique a guide wire-catheter system into a selectedrelatively peripheral artery, for example arteria radialis, arteriaulnaris or arteria brachialis to provide a high amount of cooledinfusion to the brain; 1202 introducing an arterial infusion catheterinto the selected artery, for example arteria radialis or arteriabrachialis by means of a guide-wire; 1204 positioning the tip of thearterial infusion catheter in a selected relatively central or brainclose artery, preferably in the right arteria subclavia, truncusbrachiocephalica, the ascending aorta, arteria carotis communis or inanother selected artery; 1206 applying a pressure from the outside onthe extremity with the peripheral artery, e.g. the arm or the leg, forexample by means of a circumferential torniquet, preventing ordecreasing peripheral circulation of the blood, when the cooled solutionis infused through the catheter; 1208 preferably introducingpercutaneously a temperature sensor, such as a thermistor or athermocouple, into a blood vessel that drains blood from the brain suchas the right and/or the left jugular veins. The temperature sensor ispreferably coupled to an externally arranged display means displayingthe measured temperature of the blood in the brain draining bloodvessel, e.g. the jugular vein(s); 1210 infusing a temperature controlledsolution, e.g., a cold or ice cold saline solution, preferably having analtered osmolarity, e.g. a low osmolarity, through the arterial infusioncatheter, by means of a supplying means such as a pumping means, e.g., aperfusion pump, to the selected site of infusion; 1212 checking thetemperature of the brain or the affected brain hemisphere by means ofthe temperature sensor sensing the temperature in the blood flow in therespective brain draining blood vessels, e.g. the respective jugularvein, thus being dependent on the brain temperature; 1214 adjusting theinfusion speed or the infusion rate, i.e. the amount of the temperaturecontrolled infusion solution supplied per unit of time, so that adesired and predetermined temperature is achieved in the brain or theaffected brain hemisphere, thus preferably dependent on the sensedtemperature.

Thus in step 1200, a guide wire-catheter system is possibly introduced,percutaneously or by surgical cut-down, into a selected blood vesselsupplying blood to the brain. Preferably, the catheter is introducedinto the right arteria radialis or the light arteria brachialis, andadvanced to the predetermined position, whereby a high concentration ofcooled blood can be supplied to the brain. In step 1202, a device forinfusion of an infusion fluid, preferably consisting of a guide wire anda heparinized and hydrophilic arterial infusion catheter is inserted.The tip of the arterial infusion catheter is in step 1204 positioned infor example the right arteria subclavia, arteria brachiocephalica or inthe ascending aorta.

An external pressure is possibly applied in step 1206 on the arm usedfor the arterial infusion catheter. The pressure is preferably achievedby means of a pressure means, for example by applying a circumferentialtourniquet around the selected arm, the pressure means can further bearranged for cooling the arm or for preventing peripheral circulation ofblood.

In step 1208 one or several temperature sensor(-s), such as a thermistoror a thermocouple, is preferably percutaneously introduced into forexample the right and/or left jugular veins. The temperature sensor ispreferably coupled to an externally arranged display means displayingthe measured temperature of the blood in the jugular vein(s) to anoperator. It should be understood that measurement of the temperature ispreferably performed in the internal jugular vein since this will moreaccurately reflect the temperature of the brain or brain hemisphere.

In step 1210 a temperature controlled infusion solution, e.g. a cold orice cold saline solution, is infused into the selected artery by meansof the arterial infusion catheter and a supplying means, such as apumping means, e.g. a perfusion pump.

Further in step 1212, the temperature of the brain or the affected brainhemisphere is controlled by means of the temperature sensor, and in step1214, the infusion speed of the infusion solution is adjusted to achievea desired and predetermined temperature in the brain or the affectedbrain hemisphere.

In one embodiment of the invention, the arterial infusion catheter has adiameter in the range of 0.3-3.3 mm (1-10 F. 1 F=0.33 mm), preferably inthe range of 1.3-2.6 mm (4-8 F). The surface of the arterial infusioncatheter is preferably coated with an anticoagulant compound to preventcoagulation of blood on the catheter surface and in the surroundings ofthe arterial infusion catheter. Further, in one embodiment of theinvention the arterial infusion catheter has an externally arrangedindication means, such as markings or diameter-changes, in order toindicate the position of the catheter tip in the selected artery, e.g.the right arteria subclavia, truncus brachiocephalicus or ascendingaorta. Thus it is possible to guide and position the catheter tip into aselected and predetermined position without using any diagnostic imagingmethod, such as a radiological method. The dimensions and positioningmarkings are preferably adapted to the size of the body of the patient.

FIG. 3 b shows schematically an example of this embodiment of theinvention applied in the arterial system of a human patient. A container301 containing a temperature controlled infusion solution 302 isconnected to an arterial infusion catheter 304. The infusion solution302 is tempered in a cooler or heater 303 or has a pre-arrangedtemperature that is maintained by means of a cooling or heating box 305.Most examples in the specification are however directed to cooling.

In this figure, the infusion catheter 304 is inserted into the rightradial artery 306 with its distal end outlet introduced up the rightsubclavian artery 308 in a position at level with the inlet of the rightcarotid artery 318. In this embodiment, a low infusion flow rate willcause the infusion solution to flow up into the right common carotid318. If the infusion rate is increased a part of the infusion solutionwill flow up into the right common carotid 318 and another part of theinfusion solution will flow down into the ascending aorta 314 and upinto the left common carotid 320. However, if the infusion rate isincreased even more, the infusion solution will flow down into thecoronary arteries, which should be avoided because of possibledetrimental effects on the cardiac performance.

In another embodiment of the invention, the infusion catheter 304 isinserted via the right arteria subclavia 308 into the truncusbrachiocepahlica 316. In the embodiment, a low infusion rate will causethe infusion solution to flow up into the right common carotid 318. Ifthe infusion rate is increased a part of the infusion solution will flowup into the right common carotid 318 and another part will flow into theascending aorta 314 and up into the left common carotid 320. However, ifthe velocity of the infusion solution is increased further, the infusionsolution will flow down into the coronary arteries, which should beavoided because of possible detrimental effects on the cardiacperformance.

In yet another embodiment of the invention, the infusion catheter 304 isintroduced via for example the left arm and the left arteria subclavia310 into the ascending aorta 314. In this embodiment, the infusionsolution will flow up into the left and right common carotids, 320 and318, respectively.

In a further embodiment of the invention, the infusion catheter 304 isintroduced into the ascending aorta 314 via arteria femoralis and theaortic arch 312, whereby the supplied infusion solution flows up in theleft and right common carotid, 320 and 318, respectively. This infusioncatheter can for example be a double lumen catheter as described below.

Further, a temperature sensor 324 is introduced into a jugular vein 322,whereby the temperature of the blood from the brain hemisphere can bemonitored and thus a measure of the temperature in the brain isachieved.

In an embodiment of the invention, the infusion catheter 304 is coupledto a perfusion apparatus that generates a pulsating flow of infusionsolution. This pulsating flow is then synchronized to the heart cyclesuch that the cool infusion solution flows up in the left and rightcarotids, 320 and 318, respectively, when the heart is in systole, i.e.when the heart is contracting and pumping blood to the arteries.

In an embodiment of the invention, the infused solution has atemperature in the interval of 0-37 degrees Celsius or in the intervalof 0-20 degrees Celsius, preferably in the interval of 0-10 degreesCelsius, and most preferably in the interval of 0-4 degrees Celsius.Preferably, the infusion solution is held or stored in room temperatureor preferably at 37 degrees Celsius and is quickly cooled just beforethe start of the infusion procedure to decrease or avoid the risk offormation of gas or air bubbles in the blood vessel when the infusionsolution is infused. In one embodiment of the invention, the infusionhas an altered osmolarity, e.g. a low osmolarity in order to lessen thecirculatory volume load of the infusion solution.

After the insertion of the arterial infusion catheter, one to two litersof infusion solution having a temperature in the range of 0-4 degreesCelsius can be infused intra-arterially without adverse circulatoryeffects, whereby a selectively lowered brain temperature is achieved ascompared to the whole body temperature control procedure. Further, insome cases a brain temperature in the interval of 15 to 37 degreesCelsius is desirable, but in other cases a brain temperature in therange of 30-37 degrees Celsius is desirable. Preferably, a braintemperature in the range of 27 to 35 degrees Celsius is desired and morepreferably a brain temperature of approximately 33 degrees Celsius.

According to an embodiment of the invention, a temperature about 30-35degrees Celsius in the brain or the affected brain hemisphere can beachieved after about 2-8 minutes, by supplying a cooled infusionsolution of a temperature in the range of 0-4 degrees Celsius at a speedin the range of 300-700 milliliters per minute. However, in anotherembodiment a speed in the range of 50-700 milliliters per minute issuitable. The achieved temperature, time and flow rate are probablydependent on body size of the patient as well as on the infusion rate.

The flow velocity of the infusion solution can optionally be regulatedin a way making the blood in the arteria vertebralis dexter and thearteria carotis dexter to perfuse with a spill-over to the arcus aortaeand to flow along the aorta curvatura major into the left caroticartery. This is desirable in order to allow the maximum share of thespill-over to reach the aorta carotis sinister. The above arrangementwill prevent flow backwards towards the valvular section.

The Maintained Temperature Control Phase

The maintained temperature control procedure, i.e., the procedure formaintaining the desired level of selected brain hypothermia orhyperthermia, can either be accomplished during or after the whole bodytemperature control procedure or the brain-selective temperature controlprocedure described above. Further, the maintained temperature controlphase can be achieved by using for example a temperature regulatedblanket or mattress or by establishing an extra-corporeal circulation oftemperature regulated blood or another temperature regulated solution.This phase is for example accomplished in hospitals wherein immediateaccess to specialized personnel in cardiology and radiology is provided.

In the inventive concept, this phase comprises a method of establishingan extra-corporeal circulation of temperature controlled blood. Themethod comprises: withdrawal or extraction of blood from a living beingfor example suffering of stroke, trauma, neonatal asphyxia orcirculatory arrest, controlling or regulating the temperature of theblood, possibly also regulating the oxygenation of the blood, andreintroducing the blood into the living being. By means of thesemeasures, the temperature of the brain and possibly the rest of the bodyare controlled. One embodiment of the method comprises the establishmentof two extra-corporeal circuits, namely a first circuit for cooling thebrain and a second circuit for heating other parts of the body, e.g. forkeeping the rest of the body at normal temperature. A variety of thisembodiment utilizes a peltier element for cooling and the opposite sideof the same peltier element for heating.

More specifically, an embodiment of the method of establishing anextra-corporeal circulation of temperature controlled blood comprisesthe steps of (cf. FIG. 4): 1300 introducing, into a central vein orartery of a patient, an extraction catheter for extraction of blood;1302 possibly, introducing a venous infusion catheter into a vein of thepatient; 1304 possibly, introducing an arterial infusion catheter intoan artery of the patient, preferably to an artery supplying blood to thebrain of the patient; 1306 possibly, introducing one or severaltemperature sensors into one or both jugular veins, whereby thetemperature(-s) of the blood in the jugular vein(-s) can be measured;1308 connecting the extraction catheter to an arterial cannula, i.e. thearterial infusion catheter, via a perfusion pump, a heat exchanger andpossibly also a regulator regulating the oxygenation of the blood,whereby an extra-corporeal circulation to an artery controlling thetemperature of the brain is established; 1310 possibly also connectingthe extraction catheter to the venous infusion catheter by means of forexample a flow-dividing Y-connector, via a second perfusion pump and aheat exchanger, whereby an extra-corporeal circulation to the venoussystem is established; 1312 circulating venous or arterial bloodextra-colporeally from the patient through the oxygenator and heatexchanger(-s), regulating or controlling the oxygenation and temperatureof the blood, and back to the patient; 1314 reintroducing temperaturecontrolled blood into the patient through the arterial infusion catheterarranged in an artery leading blood to the brain, whereby thereintroduced blood regulates the oxygenation and temperature of thebrain; 1316 optionally, reintroducing temperature controlled blood intothe patient through the venous infusion catheter arranged in the vein,whereby the reintroduced blood regulates the temperature of the rest ofthe body; 1318 maintaining the extra-corporeal circulation regulatingthe temperature at the desired temperature levels of the brain for adesired period of time thereafter; 1320 possibly, optimizing theviscosity of the blood by infusing a saline solution or byhemofiltration; and 1322 applying a heating or cooling blanket in orderto maintain a desired body temperature level over an extended period oftime.

In step 1300, a blood extraction means is inserted into a suitable veinor artery, e.g., vena femoralis or arteria femoralis or vena jugularis.The blood extraction device is in one embodiment of the invention anintroducer or a first catheter. For example an extraction catheterhaving an outer diameter smaller than the normal inner diameter of thevein or the artery, so as not to stop entirely the flow of blood aroundthe extraction catheter, but large enough to give a sufficient flow ofextracted blood. The vein or artery is e.g. the vena femoralis orarteria femoralis or vena jugularis. For an adult patient an outerdiameter of approximately 2.6-4.6 mm (8-14 F) and an inner diameter aslarge as possible in the relation to the outer diameter would besufficient. For children or grown-ups with other vein or arterydimensions, the dimensions of the catheter will obviously have to bemodified accordingly. The catheter has in one embodiment of theinvention, a conical extra-corporeal coupling for low flow resistanceduring perfusion. This coupling is provided with a seal that can beperforated, for example by a guide wire and/or a dilator, to preventunnecessary bleeding. The seal can also be removed for attachment to anextra-corporeal circuit. Preferably, the catheter is heparinizedinternally and externally, to counteract coagulation of the blood thatcomes into contact with the catheter.

In step 1302, an infusion device is introduced possibly into asufficiently large peripheral or central vein. The infusion device, ispreferably an infusion catheter for the reintroduction or reinfusion oftemperature regulated blood or for infusion of a treatment solution.This infusion catheter is primarily intended for the reinfusion ofpossibly heated extra-corporeally circulated blood, whereby theundesirable cooling effects of the rest of the body may be postponed orcompletely counteracted.

In step 1304, an arterial infusion catheter is possibly introduced in aperipheral artery and its tip positioned into an artery supplying bloodto the brain. The arterial infusion catheter can be the one used in forexample a previous selective brain temperature control phase, whereby itis not necessary to introduce another arterial infusion catheter.However, another arterial infusion catheter can optionally beintroduced, for example a double lumen catheter (cf. FIG. 5), whichpreferably is introduced into the ascending aorta via a femoralisartery. Thus, the optionally introduced arterial infusion catheter caneither be used alone or together with another arterial infusioncatheter, for example together with an arterial infusion catheterintroduced via the left or right arteria subclavia.

In FIG. 5, an exemplifying embodiment of a double lumen catheter 500 isshown. The double lumen catheter has an outer diameter of about 2.7 mmand a first inner lumen 501 having a diameter of about 2.1 mm. In thewall of the catheter is an extra lumen, viz a second inner lumen 502having a diameter of about 0.3 mm. The distal end of the catheter tapersover a distance of about 3 cm to 1.3 mm still containing the smallsecond inner lumen. The large first inner lumen ends about 4 cm from thetip. The catheter is shaped as a right coronary artery catheter.Extending from the catheter tip and over a distance of approximately 5cm are a number, for example eight, side holes 503 to the greater lumenof the catheter arranged along the greater curvature of the catheter.The side holes have a diameter of about 1.5 mm.

When the catheter is in position, the tip of the catheter 500 ispositioned slightly above the entrance of the left coronary artery andthe side holes to the greater lumen are arranged against the rightbrachiocephalic artery and left carotid artery. By infusion of aninfusion solution, such as temperature controlled or regulated blood ora temperature controlled solution at high infusion rate (5-10 ml persecond) by means of the larger first inner lumen 501, the infusionsolution will flow through the holes 503 against the rightbrachiocephalic and left carotid artery, whereby rather selectivecooling of the brain can be achieved for inducing or maintainingtemperature control.

If necessary, the catheter 500 can be advanced some further centimeters,whereby the tip enters the left coronary artery and pharmacologicalcompounds or radiological contrast may be administered locally to theheart by means of the second inner lumen 502.

At least one temperature sensor or a thermistor is in step 1306 insertedpreferably percutaneously into a jugular vein, whereby the temperatureof the blood in the vein can be measured. However, in one embodiment ofthe invention two temperature sensors are arranged in vena jugularis,sinister and dexter, respectively. By means of the temperature sensorsgood temperature regulation of the brain is supported. Through the venajugularis interna, the blood is transported away from the brain, and thethermistor gives off a signal that reflects the temperature of the bloodleaving the brain, thus indicating the temperature of the brain or brainhemisphere being thermally regulated. The thermistor preferably consistsof some suitable disposable material, which preferably is heparinized.The dimensions of the part inserted into the vena jugularis internashould be small enough to prevent any significant obstruction of thevenous blood flow.

The output of the thermistor may be used in different ways. In oneembodiment, the signal is transferred to a regulator, which controls theheat exchanger or the circulation pump or both, in order to achieve aregulated temperature level in the selected brain hemisphere.Alternatively, or in addition, the signal may be transferred to anindicating device, such as a visual display showing the currenttemperature of the blood in the vena jugularis interna, and hence theapproximate temperature of the brain or the selected brain hemisphere.

In step 1308, the extraction catheter is connected to the arterialcannula, i.e. the return device or the arterial infusion catheter, via aperfusion pump, a heat exchanger and possibly also a regulatorregulating the oxygenation of the blood, thereby establishing anextra-corporeal circulation circuit for temperature regulated blood.

Thus the inlet of a blood conduit such as a blood tube is attachedaccording to prior art to the other opening of the extraction catheter,and the tube is passed through a perfusion pump. The blood tubepreferably consists of an internally heparinized biocompatible plasticmaterial, and has a diameter suited to its purpose. The blood tubepasses through a circulation pump according to prior art, a so-calledperfusion pump, preferably equipped with rollers exerting a peristalticeffect externally on the tube.

The blood tube extends from the pump to a heat exchanger, which in thisparticular embodiment is arranged for cooling the blood, but which inanother embodiment may be arranged for heating it or it can be arrangedfor both heating and cooling. In one type of heat exchanger the bloodtube passes through a device which supplies or removes heat energy fromthe blood through the walls of the blood tube. In another type of heatexchanger, the blood tube is attached to a heparinized heat-exchangingbag with blood canals, providing a large surface area forheating/cooling.

In the embodiment intended for the treatment of stroke or circulatoryarrest, the heat exchanger should be capable of regulating blood to atemperature between 0 and 37 degrees Celsius. In some cases, a smalltemperature fall of only a few degrees is desirable, for example acooling to 34 degrees Celsius. In other cases a larger temperature fallis desirable, such as down to 0-5 degrees Celsius. Within other areas ofapplication, a heating of the blood may be desirable, such as from 37degrees Celsius to about 40 degrees Celsius. As the brain or selectedbrain hemisphere is cooled/heated, the general body temperature alsofalls/rises, and accordingly the temperature of the extracted blood. Theheat exchanger is therefore controlled so as to keep the blood returnedto the body after cooling/heating at the desired temperature.

Optionally, the blood conduit may be attached to a per se knownoxygenator or a deoxygenator, before or after the heat exchanger, inorder to oxygenate or to deoxygenate the blood.

One outlet end of the extra-corporeal blood circuit is attached to theproximal end of the arterial infusion catheter reaching into the rightarteria subclavia, truncus brachiocephalicus, ascending aorta or arteriacarotis communis, from the heat exchanger or in relevant cases from theoxygenator or deoxygenator, which completes the configuration of thetemperature controlling system and makes it ready for use.

In an embodiment of the present invention, the circulation pump isplaced in the proximity of the place of extraction of blood, but it canalso be placed elsewhere in the extra-corporeal blood circuit, forexample immediately before the blood return catheter. In such a case,the rest of the blood conduit should be primed before starting theinfusion of the infusion solution.

In one embodiment of the invention (cf. FIG. 8), an open reservoir 926containing, for example, priming solution, such as a saline solution orblood, is arranged between the extraction catheter 922,924 and thecirculation pump or the perfusion pump 928, and a shunt 938, in the formof an internally heparinized blood tube, has been arrangedextra-corporeally to create a connection from one section between theextraction catheter 922,924 and the reservoir 926 to another sectionbetween the artery catheter/infusion catheter 934, 940 and the heatexchanger 932 or the oxygenator/deoxygenator 930. By closing the flow ofblood via the extraction catheter 922 and opening the flow from theartery catheter 940, blood will flow out of the arterial catheter 934,and will be pumped by the circulation pump 928 to the reservoir 926,whereby the system will be purged of any air present. Any air present atthe extracted blood side, i.e. the venous side or the arterial side, canthen be removed similarly by stopping the flow of blood to/from theartery and using the circulation pump 928 to make the extracted bloodand air flow to the reservoir 926. When the system has been purged ofair, the blood flow through the shunt 938 is stopped, for example bymeans of an artery forceps, and the circulation of blood can be startedand the temperature of the brain can be monitored by means of atemperature sensor 942 arranged in a jugular vein of the patient 920.

As the brain is continuously selectively cooled, the general bodytemperature also falls, possibly to undesirable levels. To counteractthis effect of brain cooling, optionally a part of the reinfusable bloodis in step 310 deviated by way of a Y-formed connector into a heatingdevice and a circulation pump and further introduced into the venoussystem of the patient. The outlet end of this part of theextra-corporeal blood circuit is attached to the proximal end of thevenous infusion catheter.

In step 1312, venous or arterial blood is circulated extra-corporeallyfrom the patient through the heat exchanger regulating the temperatureof the blood and back to the patient. Thus, when the system fortemperature control has been configured, circulation of blood throughthe extra-corporeal circuit is started, involving the extraction ofblood from the vein or artery, cooling or heating it to the desiredtemperature in the heat exchanger(-s), for example to a temperaturebetween 0 and 37 degrees Celsius, optionally regulating oxygenation bymeans of an oxygenator, and finally reintroducing it into the patientvia the arterial infusion catheter. The temperature controlled bloodflows from there into the brain or the affected brain hemisphere, whichtemperature is controlled swiftly and efficiently.

In step 1314, the temperature controlled blood is reintroduced into thepatient through the arterial infusion catheter arranged in an arteryleading blood to the brain, whereby the reintroduced blood regulates theoxygenation and temperature of the brain or the selected brainhemisphere.

In step 1316, heated blood, having a temperature in the range of 37-40degrees Celsius, is optionally reintroduced into the patient through thevenous infusion catheter, whereby undesired general cooling effects onthe rest of the body are diminished.

In step 1318, the temperature regulated extra-corporeal circulation ismaintained at the desired temperature levels of the brain or theaffected brain hemisphere for a desired period of time thereafter.

In step 1320, the viscosity of the blood can possibly be optimized byinfusing a saline solution diluting the blood or by hemofiltrationconcentrating the blood.

In step 1322, external cooling by the means of a cooling blanket may beused for the maintenance of the desired temperature over an extendedperiod of time, also after intra-arterial perfusion has been stopped.Optionally, the blanket may be used for heating the rest of the bodyduring an extended period of intra-arterial perfusion with coolingperfusate, intended for maintenance of local brain hypothermia.

FIG. 6 a shows schematically an embodiment of the maintained temperaturecontrol phase applied in a human patient. An extraction catheter 600 forextraction of blood is introduced into a central vein or artery of apatient, for example in a femoralis vein 602. Further, a venous catheter604 is inserted into a vein of the patient, for example the right medianvein 606. The extraction catheter 600 is further connected to the venouscatheter 604 via a perfusion pump 612, an oxygenator/dexoygenator 614and a temperature regulator 616, whereby a blood circuit is establishedsupplying heated extracted blood to the patient through the venouscatheter 604.

In this embodiment an arterial infusion catheter 304 is introduced intothe truncus brachiocephalica 316 through the right radial artery 306 andvia the right subclavian artery 308. Further, the arterial infusioncatheter is connected to the extraction catheter 600 via the perfusionpump 612, the oxygenator/deoxygenator 614 and the temperature regulator616, whereby a blood circuit is established supplying cooled extractedblood to the patient via the truncus brachiocephalica 316.

As schematically illustrated in the figure, a temperature sensor 608 isintroduced into a jugular vein 610 and possibly connected to a controlunit 618 regulating the temperature regulator 616 cooling the extractedblood, whereby the cooling of the brain is controlled or monitored.

In another embodiment of the invention as schematically illustrated inFIG. 6 b, an arterial infusion catheter 500 is inserted into theascending aorta 314 via the left femoral artery 620 and the aortic arch312. In this embodiment, the cooling blood circuit is establishedbetween the extraction catheter 600 and the arterial infusion catheter500 via the perfusion pump 612, the oxygenator/deoxygenator 614 and thetemperature regulator 616. Further, in this embodiment the arterialinfusion catheter 500 is the double lumen catheter described withreference to FIG. 5, but it should be understood that the arterialcatheter also can be another kind of catheter and alternatively placedin a common carotid artery under the protection of an embolus filterdevice.

In yet another embodiment of the invention as schematically illustratedin FIG. 6 c, three extra-corporeal blood circuits are established. Thisembodiment of the invention is a combination of the two embodimentspreviously described with reference to FIGS. 6 a and 6 b. Firstly, anextra-corporeal blood circuit for heated blood is established betweenthe extraction catheter 600 and the venous infusion catheter 604 via theperfusion apparatus 612, the oxygenator/deoxygenator 614 and thetemperature regulating 616. Secondly, an extra-corporeal blood circuitfor cooled blood is established between the extraction catheter 600 andthe arterial infusion catheter 304 via the perfusion apparatus 612, theoxygenator/deoxygenator 614 and the temperature regulating 616. Thirdly,a third extra-corporeal blood circuit for cooled blood is establishedbetween the extraction catheter 600 and the arterial infusion catheter500 via the perfusion apparatus 612, the oxygenator/deoxygenator 614 andthe temperature regulating 616. Thus, in this embodiment having twoextra-corporeal blood circuits for cooled blood, a more efficientcooling of the brain is achieved.

Further, in embodiments of the invention the perfusion apparatus 616 isarranged to generate a pulsating flow of infusion solution. Thispulsating flow is then synchronized to the heart cycle such that thecooled infusion solution flows up in the left and right carotids, 320and 318, respectively, when the heart is in systole, i.e. when the heartis contracting and pumping blood to the arteries.

According to another embodiment of the invention, the infusion catheterdescribed above can be positioned in the internal jugular vein on oneside of the neck. The infusion catheter is preferably positioned withits tip directed cranially. This can be accomplished by means ofpuncturing the internal jugular vein with a needle. A guide wire canthen be introduced through the needle and into the vein in the cranialdirection and an introducer, e.g. an introducer of approximately 9French, is placed into the vein.

According to an embodiment, the infusion catheter is a triple lumenballoon catheter 1000, cf. FIG. 9, is placed through the introducer andplaced with the balloon 1002 at the level of the angle of the mandible.The triple lumen balloon catheter 1000 can for example be an 8 Frenchcatheter having a length of approximately 25 centimeters. The threelumens are intended for introduction of a pressure recording means, forinfusion of a brain-protective fluid and for inflation/deflation of theballoon.

By means of a pressure recording means inserted via a first lumen 1004of the catheter 1000, the pressure in the jugular vein can monitored.The first lumen 1004 ends approximately 1.5 cm proximally of thecatheter tip.

A Y-connector can be attached to preferably the stopcock of a secondlumen 1006 of the catheter 1000. Further a temperature sensor, e.g. athin wire with a thermistor, can be placed through one of the arms ofthe Y-connector and through the second lumen 1006 and placedapproximately 3 centimeters distally of the tip of the catheter 1000 inorder to measure the temperature of the infused fluid. The measuredtemperature can further be an indication of the presence of systemicblood, i.e. that the balloon does not seal off the vein, since thissystemic blood will heat a cooled infusion fluid. Alternatively thethermistor may be preimbedded into the material composing the catheter1000.

Cold cristalloid solution is infused through a second lumen 1006 of thecatheter 1000 with its balloon 1002 inflated, which balloon 1002 isinflated and deflated by means of a third lumen 1008. The infusion rateis regulated in order not to have the vein pressure to exceed about 25mmHg. The infusion of cristalloid solution is subsequently followed bythe infusion of blood extracted from the remaining jugular veins or thefemoral veins or arteries. The blood has passed through a cooler,possibly a pump and possibly an oxygenator/deoxygenator passed to thecatheter in the jugular vein.

According to this embodiment a double lumen catheter, e.g. anapproximately 16 French double lumen catheter, is placed through one ofthe femoral veins into the inferior vena cava. A first lumen endsapproximately 25 mm from the tip of the catheter. A thermistor at theopening of the first lumen is recording the temperature of the blood inthe distal part of the inferior vena cava. Blood is then aspirated fromthe first lumen with a pump, passed through a heater and infused throughthe tip of the infusion catheter via a second lumen of the infusioncatheter. Temperature is in this way automatically regulated in theinferior vena cava to stay between approximately 37 and 36 degreesCelsius. However, blood can also extracted from a femoral artery and theblood flow from the femoral artery can be controlled by a flowcontroller (not shown) arranged at the catheter in the internal venajugularis causing the blood to flow due to the pressure difference inthe artery and the vein, respectively. Thus, in such an embodiment thepump is not necessary.

Further, as an alternative to the double lumen catheter in the femoralvein, a double lumen catheter can be introduced into the superior venacava via the other internal vena jugularis.

The Temperature Regulating Device

In one embodiment of the invention as schematically illustrated in FIG.7 a, the temperature regulating device or temperature regulator 700comprises a peltier element 702 and a heat exchanger such as a tube or aconduit 704 of for example folded, twisted or wrinkled stainless steelor another material able to transfer thermal energy. The conduit 704confines a passage 706 for fluid to be temperature regulated. Thus theconduit 704 has an inlet 710 for fluid to be temperature regulated andan outlet 712 for temperature regulated fluid. If the fluid is to becooled the conduit 704 should be arranged on the cool side of thepeltier element 702 and if the fluid is to be heated the conduit 704should be arranged on the hot side of the peltier element 702.

In another embodiment of the invention as schematically illustrated inFIG. 7 b, a cooling flange 720 is further arranged at the hot side ofthe peltier element 702, which cooling flange 720 is connected to a fallor another cooling device, e.g. a ventilator 722, whereby the hot sideof the peltier element 702 is cooled.

In another embodiment of the invention as schematically illustrated inFIG. 7 c, the temperature regulating device 700 is used for both coolingand heating a fluid. In this embodiment, the temperature regulatingdevice 700 is designed as a double heat exchanger comprising a peltierelement 702 and two conduits 704,704′ confining passages 706,706′ havinginlets 710,710′ and outlets 712,712′. In this embodiment, fluid passingthough the passages 706,706′ is cooled and heated, respectively.

Further, the temperature regulating device 700 is provided with a powersupply 716 supplying power to the peltier element and a control unit 718controlling the temperature regulation.

In one embodiment of the invention, the conduit 704 or the conduits704,704′ is/are provided with a plastic or plastic-like housing or cover708 or covers 708, 708′, by means of which the conduit 704 or conduits704,704′ is/are arranged to be attachable and detachable at the peltierelement 702. In this embodiment the conduit 704,704′ and the cover708,708′ is preferably manufactured as a disposable or disposables,preferably as a sterile disposable or disposables provided with forexample an anticoagulant agent on the inner surface of the conduit704,704′.

However, in another embodiment of the invention, the temperatureregulating device 700 is manufactured as a disposable and preferably asa disposable having sterile inner surfaces of the conduit 704,704′ notto contaminate the fluid to be temperature regulated and inner surfacesprovided with an anticoagulant agent.

The present invention has been described above with reference toexemplifying embodiments, and it is obvious to a person skilled in theart that the invention may be modified in other ways within the scope ofthe appended claims.

1-77. (canceled)
 78. A method for brain hypothermia, comprising thesteps of: inserting into a blood vessel an extraction catheter forextraction of blood; inserting a first infusion catheter into aninternal jugular vein, said first infusion catheter being placed withits tip directed cranially; establishing a first extra-corporeal bloodcircuit for cooled blood between said extraction catheter and said firstinfusion catheter via a pumping means and a temperature regulatingdevice capable of cooling extracted blood; extracting blood from saidblood vessel via said extraction catheter; cooling said extracted bloodby means of said temperature regulating device; infusing said cooledextracted blood to the brain via said first infusion catheter; andmaintaining cooling and circulation of blood in said firstextra-corporeal circuit for a selected period of time.
 79. The method ofclaim 78, further comprising the step of placing a balloon of said firstinfusion catheter at the level of the angle of the mandible.
 80. Themethod of claim 78, further comprising the steps of introducing apressure recording means via a first lumen of said first infusioncatheter means; and monitoring the pressure in the jugular vein by meansof said pressure recording means.
 81. The method of claim 80, furthercomprising the step of regulating the infusion rate in order to providea vein pressure that is lower than about 25 mmHg.
 82. The method ofclaim 78, further comprising the step of deflating and inflating saidballoon by means a third lumen of said first infusion catheter.
 83. Themethod of claim 78, wherein said extraction catheter is placed throughone of the femoral veins into the inferior vena cava.
 84. The method ofclaim 83, further comprising the step of placing a thermistor at the endopening of a first lumen of said extraction catheter and by means ofsaid thermistor recording the temperature of the blood in the distalpart of the inferior vena cava.
 85. The method of claim 78, furthercomprising the steps of: inserting a double lumen catheter into a veinof the venous system; establishing a second extra-corporeal bloodcircuit between a first lumen of said double lumen catheter and a secondlumen of said double lumen catheter via said pumping means and saidtemperature regulating device capable of heating extracted blood;leading an amount of said extracted blood from said blood vessel viasaid first lumen of said double lumen catheter into said secondextra-corporeal blood circuit; heating said amount of extracted blood;infusing said heated amount of extracted blood to said venous system viasaid second lumen of said double lumen catheter; and maintaining heatingand circulation in said second extra-corporeal blood circuit for aselected period of time.
 86. The method of claim 78, further comprisingthe step of automatically regulating the temperature of the infusedblood in dependence of the brain temperature or the body temperature.87. The method of claim 85, further comprising the step of automaticallyregulating the temperature of the infused blood in dependence of thebrain temperature or the body temperature.
 88. The method of claim 78,further comprising the step of providing a heating blanket configured tokeep the body temperature at a desired temperature during brainhypothermia.
 89. An infusion catheter for use in a method for brainhypothermia according to claim 78, said infusion catheter beingconfigured for insertion into an internal jugular vein with its tipdirected cranially and comprising a first lumen ending approximately 1.5cm proximally of the tip of the infusion catheter and configured to beconnected to means for recording the pressure in said vein, a secondlumen for infusion of an infusion solution, and a third lumen connectedto a balloon and configured to inflate and deflate said balloon.
 90. Theinfusion catheter of claim 89, wherein said balloon is arrangedproximally of said end opening of said first lumen.
 91. An equipment forbrain hypothermia, comprising: an extraction catheter being configuredto be inserted into a blood vessel for extraction of blood; a firstinfusion catheter according to claim 89, said first infusion catheterbeing configured for insertion into an internal jugular vein and to beplaced in said internal jugular vein with its tip directed cranially;coupling means for establishing an first extra-corporeal blood circuitfor cooled blood between said extraction catheter and said firstinfusion catheter via a pumping means and a temperature regulatingdevice capable of cooling extracted blood; and said equipment beingconfigured to: extract blood from said blood vessel via said extractioncatheter leading an amount of said extracted blood into said firstextra-corporeal blood circuit; cool said amount of said extracted blood;infuse said cooled extracted blood to the brain via said first infusioncatheter; and maintain cooling and circulation in said firstextra-corporeal blood circuit for a selected period of time.
 92. Anequipment for brain hypothermia, comprising: an extraction catheterbeing configured to be inserted into a blood vessel for extraction ofblood; a first infusion catheter according to claim 90, said firstinfusion catheter being configured for insertion into an internaljugular vein and to be placed in said internal jugular vein with its tipdirected cranially; coupling means for establishing an firstextra-corporeal blood circuit for cooled blood between said extractioncatheter and said first infusion catheter via a pumping means and atemperature regulating device capable of cooling extracted blood; andsaid equipment being configured to: extract blood from said blood vesselvia said extraction catheter leading an amount of said extracted bloodinto said first extra-corporeal blood circuit; cool said amount of saidextracted blood; infuse said cooled extracted blood to the brain viasaid first infusion catheter; and maintain cooling and circulation insaid first extra-corporeal blood circuit for a selected period of time.93. The equipment of claim 91, further comprising: a double lumencatheter being configured to be inserted into a vein of the venoussystem; and said equipment further being configured to: establish asecond extra-corporeal blood circuit for heated blood between a firstlumen of said double lumen catheter and a second lumen of said doublelumen catheter via said pumping means and said temperature regulatingdevice capable of heating extracted blood; lead an amount of saidextracted blood from said blood vessel via said first lumen of saiddouble lumen catheter into said second extra-corporeal blood circuit;heat said amount of said extracted blood; infuse said heated amount ofextracted blood to said venous system via said second lumen of saiddouble lumen catheter; and maintain heating and circulation in saidsecond extra-corporeal blood circuit for a selected period of time. 94.The equipment of claim 92, further comprising: a double lumen catheterbeing configured to be inserted into a vein of the venous system; andsaid equipment further being configured to: establish a secondextra-corporeal blood circuit for heated blood between a first lumen ofsaid double lumen catheter and a second lumen of said double lumencatheter via said pumping means and said temperature regulating devicecapable of heating extracted blood; lead an amount of said extractedblood from said blood vessel via said first lumen of said double lumencatheter into said second extra-corporeal blood circuit; heat saidamount of said extracted blood; infuse said heated amount of extractedblood to said venous system via said second lumen of said double lumencatheter; and maintain heating and circulation in said secondextra-corporeal blood circuit for a selected period of time.
 95. Theequipment of claim 91, further comprising means for automaticallyregulating the temperature of the infused blood in dependence of thebrain temperature or the body temperature.
 96. The equipment of claim93, further comprising means for automatically regulating thetemperature of the infused blood in dependence of the brain temperatureor the body temperature.
 97. The equipment of claim 91, furthercomprising a heating blanket configured to keep the body temperature ata desired temperature during brain hypothermia.